S166: KER-050 TREATMENT IMPROVED MARKERS OF ERYTHROPOIETIC ACTIVITY AND HEMATOPOIESIS OVER SIX MONTHS WHICH RESULTED IN HEMATOLOGICAL RESPONSES ACROSS A BROAD, LOWER-RISK MDS POPULATION
Authors: Aristoteles Giagounidis, Thomas Cluzeau, María Díez Campelo, David Ross, Lynette Chee, Shuhying Tan, Christine Graham, Wei Feng, Ming Yang, Ying Jiang, Miranda Ross, Allie Mcginty, Suresh Bobba, Christopher Rovaldi, Simon Cooper, Jen Salstrom
Journal: HemaSphere (2023)

Background: Myelodysplastic syndromes (MDS) are a heterogeneous group of bone marrow disorders characterized by ineffective hematopoiesis, progressive cytopenias and increasing dependence on red blood cell transfusions. Greater transfusion burden reflects diminished erythropoietic capacity of the bone marrow. For patients with high transfusion burden (HTB), currently available treatments such as Erythropoiesis Stimulating Agents or Erythroid Maturation Agents show limited efficacy. Response is further influenced by factors such as endogenous erythropoietin (EPO) level and ring sideroblast (RS) status. KER-050 is an investigational, modified activin receptor type IIA ligand trap designed to inhibit select TGF-β superfamily ligands (activins A and B, GDFs 8 and 11) and restore balance to the osteohematopoietic niche (OHN). In preclinical findings, KER-050 acted on early and late-stage erythropoietic progenitors. Clinically, KER-050 was associated with increases in hematopoiesis markers and hematological responses in participants with lower-risk MDS, irrespective of RS and transfusion status. Aims: To characterize changes in hematopoiesis markers over 6 months and hematological responses with KER-050 treatment Methods: Interim results are presented from an ongoing Phase 2 study evaluating the safety and tolerability of KER-050 in patients with lower-risk MDS. Secondary efficacy endpoints include IWG 2006 HI-E and transfusion independence (TI) over 8 weeks. Exploratory evaluations of hematopoiesis markers over 6 months of treatment are presented for the first time. All participants provided informed consent. Data are presented from participants dosed at the recommended part 2 dose (RP2D; 3.75 – 5 mg/kg every 4 weeks) as of October 1, 2022. Results: The RP2D population (N=36) included 13 (36%) non-RS and 20 (56%) HTB participants. Mean treatment duration was 28 weeks, with 79% (23/29) of HI-E or TI evaluable participants ongoing. Safety data are presented in Table 1. The most frequent adverse events (AEs) were diarrhoea (22%), fatigue (19%) and dyspnoea and nausea (17% each). Rates of HI-E and TI (Table 2) demonstrated potential for KER-050 to improve anemia regardless of RS and transfusion status. Baseline levels of soluble transferrin receptor (sTfR) indicated that non-RS participants showed diminished erythropoietic capacity relative to RS+ participants (Fig. 1 A, B). KER-050 treatment resulted in sustained increases in hemoglobin and platelets over 6 months in HI-E and/or TI responders (Fig. 2). Increases in sTfR were also observed in the RP2D population. Increases were greater in HTB participants where sTfR continued to rise over the first 16 weeks and were maintained through 24 weeks (Fig. 3). At the individual level, 2 HTB participants (1 RS+,1 non-RS) exhibited sustained increases in sTFR over at least 6 months that paralleled increases in hemoglobin and periods of HI-E or TI. In the participant with elevated baseline ferritin, observed decreases in ferritin suggest reduction of iron overload (Fig. 4). Summary/Conclusion: Based on interim findings from this Phase 2 study as of the data cut-off date, KER-050 was generally well-tolerated with longer-term treatment and has the potential to drive hematological improvement and reduce transfusion burden in a broad, lower-risk MDS population. By modulating TGF-β superfamily ligands, KER-050 may over time restore a healthy OHN and reduce iron overload to support normal hematopoiesis, even in heavily transfused patients. Enrollment is ongoing and updated safety and efficacy results will be reported at the meeting.Keywords: Myelodysplastic syndrome, Iron overload, Erythropoieisis, Hematopoiesis